17-65153443-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_003835.4(RGS9):c.79A>G(p.Met27Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (1 hom.)
• Consequence: RGS9 NM_003835.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

Genes affected

RGS9 (HGNC:10004): (regulator of G protein signaling 9) This gene encodes a member of the RGS family of GTPase activating proteins that function in various signaling pathways by accelerating the deactivation of G proteins. This protein is anchored to photoreceptor membranes in retinal cells and deactivates G proteins in the rod and cone phototransduction cascades. Mutations in this gene result in bradyopsia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029693425).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000256 (39/152338) while in subpopulation AMR AF= 0.00242 (37/15306). AF 95% confidence interval is 0.0018. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS9	NM_003835.4	c.79A>G	p.Met27Val	missense_variant	2/19	ENST00000262406.10
RGS9	NM_001081955.3	c.79A>G	p.Met27Val	missense_variant	2/19
RGS9	NM_001165933.2	c.79A>G	p.Met27Val	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS9	ENST00000262406.10	c.79A>G	p.Met27Val	missense_variant	2/19	1	NM_003835.4	P4

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249572 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461812 Hom.: 1 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000487

ExAC AF: 0.0000497 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 27 of the RGS9 protein (p.Met27Val). This variant is present in population databases (rs201444204, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RGS9-related conditions. ClinVar contains an entry for this variant (Variation ID: 858339). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RGS9 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	25
Dann	Benign	0.97
DEOGEN2	Uncertain	0.47	T;.;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
Polyphen		1.0, 0.99	.;.;D;D
Vest4		0.87, 0.86
MVP		0.77
MPC		0.75
ClinPred		0.48	T
GERP RS		5.5
Varity_R		0.44
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201444204; hg19: chr17-63149561;